Classification of Antineoplastic Chemotherapeutic AgentsConventional cytotoxic antineoplastic agents can be grouped by biochemical mechanism of action into the following general categories: alkylating agents, antimetabolites, mitotic inhibitors, antineoplastic antibiotics, hormonal agents, and miscellaneous. The clinically relevant drugs used in veterinary medicine are discussed below, and the indications, mechanism of action, and toxicities of selected agents. .

Mechanisms of Action, Indications, and Toxicities of Selected Antineoplastic AgentsDrug Mechanism of Action Major Indications Toxicities

Alkylating Agent -  a substance that causes replacement of hydrogen by an alkyl group especially in a biologically important molecule; specifically :  one with mutagenic activity that inhibits cell division and growth and is used to treat some cancers

Cyclophosphamide Undergoes hepatic biotransformation to active metabolites that alkylate DNA; alkylation leads to miscoding of DNA and cross-linking of DNA strands.

Lymphoma, mammary adenocarcinoma, sarcomas, lymphocytic leukemia

Nausea, vomiting (infrequent), moderate to severe myelosuppression, sterile hemorrhagic cystitis

Melphalan Alkylates DNA causing miscoding and cross-linking of DNA strands

Multiple myeloma Nausea, vomiting, anorexia, moderate myelosuppression (may be more myelosuppressive in cats)

Chlorambucil Alkylates DNA causing miscoding and cross-linking of DNA strands; slowest-acting alkylating agent

Chronic lymphocytic leukemia, small-cell lymphoma

Nausea, vomiting, mild to moderate myelosuppression

Lomustine (CCNU) Alkylates DNA causing miscoding and cross-linking of DNA strands; inhibits both DNA and RNA synthesis; not cross-resistant with other alkylating agents

Lymphoma, mast cell tumor, histiocytic sarcoma, CNS neoplasia’s, multiple myeloma

Nausea, vomiting, moderate to severe myelosuppression (may be delayed for 4–6 wk), hepatotoxicity, nephrotoxicity, pulmonary toxicity

Streptozotocin Inhibits DNA synthesis; high affinity for pancreatic β cells

Insulinoma Severe, potentially fatal nephrotoxicity (if given without diuresis) and hepatotoxicity, nausea (immediate and delayed), vomiting, mild myelosuppression

Dacarbazine (DTIC) Undergoes hepatic biotransformation to active metabolites that alkylate DNA; inhibits RNA synthesis

Lymphoma, sarcomas Severe acute nausea, vomiting, phlebitis, moderate myelosuppression, hepatotoxicity, anecdotal reports of pleural effusion in cats

Ifosfamide Analogue of cyclophosphamide; undergoes hepatic biotransformation to active metabolites that alkylate DNA; alkylation leads to miscoding of DNA and cross-linking of DNA strands

Various sarcomas Nausea, vomiting, myelosuppression, sterile hemorrhagic cystitis, possible nephrotoxicity

Antimetabolites - A drug that is similar enough to a natural chemical to participate in a normal

biochemical reaction in cells but different enough to interfere with the normal division and functions of cells. So named because the drug inhibits a normal metabolic process.

Methotrexate Inhibition of dihydrofolate reductase that is required for formation of tetrahydrofolate, a necessary cofactor in thymidylate synthesis; thymidylate essential for DNA synthesis and repair

Lymphoma Nausea, vomiting, moderate myelosuppression, GI ulceration, hepatotoxicity, pulmonary toxicity

5-Fluorouracil Pyrimidine analogue; interferes with DNA synthesis and may be incorporated into RNA to cause toxic effects

Carcinomas (systemic); cutaneous carcinomas (topical)

Systemic: nausea, vomiting, moderate myelosuppression, neurotoxicity, GI ulceration, neurotoxicity, hepatotoxicity Topical: local irritation, pain, hyperpigmentation Cannot be given to cats (fatal neurotoxicity)

Cytarabine Pyrimidine analogue; incorporates into DNA causing steric hindrance and inhibition of DNA synthesis

Lymphoma (including CNS), leukemias; no activity in solid tumors

Nausea, vomiting, moderate myelosuppression, nephrotoxicity, hepatotoxicity

Gemcitabine Pyrimidine analogue; incorporates into DNA causing steric hindrance and

Limited efficacy seen in lymphoma and various carcinomas

Mild nausea, vomiting, mild to moderate myelosuppression, pulmonary toxicity,

inhibition of DNA synthesis

nephrotoxicity

Antibiotic Antineoplastics

Doxorubicin Intercalates and binds to DNA, disrupting helical structure and DNA template; inhibits RNA and DNA polymerases; causes DNA topoisomerase II–mediated chain scission; generates free radicals that cause DNA scission and cell membrane damage

Lymphoma, leukemia, multiple myeloma, osteosarcoma, hemangiosarcoma, and various other sarcomas and carcinomas

Nausea, vomiting, moderate myelosuppression, hemorrhagic colitis, severe cutaneous reactions if extravasated; red urine (not hematuria), transient ECG changes and arrhythmias, nephrotoxicity, anaphylactoid reactions Cumulative dose-related congestive heart failure in dogs; cumulative nephrotoxicity in cats

Mitoxantrone Topoisomerase II–mediated chain scission; DNA aggregation, oxidation, and strand breakage

Lymphoma, various carcinomas

Nausea, vomiting, moderate to severe myelosuppression, diarrhea, bluish discoloration to sclera; less severe adverse effects than others in this group

Bleomycin Mixture of glycopeptides; generates oxygen radicals that cause chain scission and fragmentation of DNA

Carcinomas Nausea, vomiting, myelosuppression, fever, allergic reactions including anaphylaxis, hyperpigmentation, skin ulceration, pneumonitis,

pulmonary fibrosis

Dactinomycin (Actinomycin D)

Intercalates and binds to DNA, disrupting helical structure and DNA template; inhibits RNA and DNA polymerases; causes DNA topoisomerase II–mediated chain scission; generates free radicals that cause DNA scission and cell membrane damage

Lymphoma, various sarcomas

Nausea, vomiting, moderate to severe myelosuppression, phlebitis; severe tissue reaction if extravasated

Mitotic Inhibitors – drugs derived from natural plant sources. They inhibit cell division or mitosis, where a single cell divides into two genetically identical daughter cells. Mitotic inhibitors bind to tubulin and inhibit its polymerization into microtubules. Microtubules are structures responsible for pulling the cell apart when it divides. Mitotic inhibitors affect cancer cells more than normal cells because cancer cells divide (mitotic cell division) more rapidly therefore are more susceptible to mitotic inhibition.

Vinblastine Binds to tubulin, leading to disruption of mitotic spindle apparatus and arrest of cell cycle

Lymphoma and leukemias, mast cell tumors

Mild nausea, vomiting, severe myelosuppression, neurotoxicity with high doses, inappropriate secretion of antidiuretic hormone

Vincristine Binds to tubulin, leading to disruption of mitotic spindle apparatus and arrest of cell cycle

Lymphoma and leukemias, transmissible venereal cell tumors, various sarcomas

Mild to moderate nausea, vomiting, mild to moderate myelosuppression, severe tissue reaction if extravasated, cumulative

peripheral neuropathy, constipation, paralytic ileus, inappropriate secretion of antidiuretic hormone

Vinorelbine Binds to tubulin, leading to disruption of mitotic spindle apparatus and arrest of cell cycle

Primary lung tumors, limited efficacy in mast cell tumors

Mild nausea, vomiting, myelosuppression

Paclitaxel Binds to tubulin, stabilizing microtubule polymer and arresting mitosis

Mammary carcinoma, squamous cell carcinoma

Myelosuppression, nausea, vomiting, hypersensitivity (when Cremor EL is used as vehicle)

Miscellaneous

Cisplatin Reacts with proteins and nucleic acids; forms cross-links between DNA strands and between DNA and protein; disrupts DNA synthesis

Osteosarcoma, carcinomas, and mesothelioma

Intense nausea, vomiting, mild to moderate myelosuppression, potentially fatal nephrotoxicity if not given with diuresis, anaphylaxis, ototoxicity, peripheral neuropathy, hyperuricemia, hypermagnesemia Cannot be given to cats (fulminant pulmonary edema)

Carboplatin Reacts with proteins and nucleic acids; forms cross-links between DNA strands and between DNA

Osteosarcoma, carcinomas

Mild nausea, vomiting, diarrhea, moderate to severe myelosuppression

and protein; disrupts DNA synthesis

L-Asparaginase Inhibits protein synthesis by hydrolyzing tumor cell supply of asparagine

Acute lymphoid leukemias and lymphoma

Hypersensitivity reactions, anaphylaxis especially after repeated doses, alteration in coagulation parameters, hepatotoxicity, pancreatitis (people), potential inhibition of immune responsiveness (B and T cells)

Mitotane (o,p′DDD) Destroys adrenal zona fasciculate and zona reticularis

Pituitary hyperadrenocorticism, palliation of adrenal cortical tumors

Nausea, vomiting, anorexia, diarrhea, adrenal insufficiency, CNS depression, dermatitis

Hydroxyurea Inhibits conversion of ribonucleotides to deoxyribonucleotides by destroying ribonucleoside diphosphate reductase

Polycythemia vera, granulocytic and basophilic leukemia, thrombocythemia, investigational for meningiomas

Nausea, vomiting, mild myelosuppression, alopecia, sloughing of claws, dysuria

Procarbazine Mechanism is unclear; inhibits DNA, RNA, and protein synthesis, perhaps through alkylation

Lymphoma, as part of MOPP chemotherapy protocol; brain tumors

Nausea, vomiting, myelosuppression, diarrhea

Hormones

Prednisone Lympholytic; inhibits mitosis in lymphocytes

Lymphoma, mast cell tumors, multiple myeloma, palliative

Sodium retention, GI ulceration, protein catabolism, muscle

treatment of brain tumors

wasting, delayed wound healing, suppression of hypothalamic-pituitary-adrenal axis, immunosuppression